Peptide YY (PYY) gene polymorphisms in the 3'-untranslated and proximal promoter regions regulate cellular gene expression and PYY secretion and metabolic syndrome traits in vivo.

Abstract

RATIONALE:

Obesity is a heritable trait that contributes to hypertension and subsequent cardiorenal disease risk; thus, the investigation of genetic variation that predisposes individuals to obesity is an important goal. Circulating peptide YY (PYY) is known for its appetite and energy expenditure-regulating properties; linkage and association studies have suggested that PYY genetic variation contributes to susceptibility for obesity, rendering PYY an attractive candidate for study of disease risk.

DESIGN:

To explore whether common genetic variation at the human PYY locus influences plasma PYY or metabolic traits, we systematically resequenced the gene for polymorphism discovery and then genotyped common single-nucleotide polymorphisms across the locus in an extensively phenotyped twin sample to determine associations. Finally, we experimentally validated the marker-on-trait associations using PYY 3'-untranslated region (UTR)/reporter and promoter/reporter analyses in neuroendocrine cells.

RESULTS:

Four common genetic variants were discovered across the locus, and three were typed in phenotyped twins. Plasma PYY was highly heritable (P < 0.0001), and genetic pleiotropy was noted between plasma PYY and body mass index (BMI) (P = 0.03). A PYY haplotype extending from the proximal promoter (A-23G, rs2070592) to the 3'-UTR (C+1134A, rs162431) predicted not only plasma PYY (P = 0.009) but also other metabolic syndrome traits. Functional studies with transfected luciferase reporters confirmed regulatory roles in altering gene expression for both 3'-UTR C+1134A (P < 0.001) and promoter A-23G (P = 0.0016).

CONCLUSIONS:

Functional genetic variation at the PYY locus influences multiple heritable metabolic syndrome traits, likely conferring susceptibility to obesity and subsequent cardiorenal disease.

• Authors: Pei-An Betty Shih, Lei Wang, Stephane Chiron, Gen Wen, Caroline Nievergelt, Manjula Mahata, Srikrishna Khandrika, Fangwen Rao, Maple M Fung, Sushil K Mahata, Bruce A Hamilton, Daniel T O'Connor
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 94 Issue 11 Pg. 4557-66 (Nov 2009) ISSN: 1945-7197 [Electronic] United States
• PMID: 19820027 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 3' Untranslated Regions
• Peptide YY

Topics

• 3' Untranslated Regions (genetics)
• Diseases in Twins (genetics)
• Exons (genetics)
• Gene Expression Regulation
• Genetic Predisposition to Disease
• Genetic Variation
• Heart Diseases (genetics)
• Humans
• Introns (genetics)
• Kidney Diseases (genetics)
• Metabolic Syndrome (genetics)
• Obesity (genetics)
• Peptide YY (genetics, metabolism)
• Polymorphism, Genetic
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Twins (genetics)